Important Safety Information About Natazia® (estradiol valerate and estradiol valerate/dienogest) Prescribing Information including Boxed WARNING for Natazia

Important Safety Information About Natazia: Women over 35 years old who smoke should not use Natazia. Smoking increases the risk of serious cardiovascular side effects from Natazia use. This risk increases with age and the number of cigarettes smoked.  Continue reading below

Natazia WARNING-CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS: Women over 35 years old who smoke should not use Natazia. Smoking increases the risk of serious cardiovascular side effects from Natazia use. This risk increases with age and the number of cigarettes smoked.

Important Safety Information About Climara Pro® (estradiol/levonorgestrel transdermal system) Prescribing Information including Boxed WARNING for Climara Pro

Important Safety Information About Climara Pro: WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA. Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia.  Continue reading below

Climara Pro® WARNING-IMPORTANT INFORMATION ABOUT COMBINING ESTROGEN AND PROGESTIN: Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes. or dementia (decline of brain function). Using estrogens with progestins may Increase your chances of getting heart attacks. strokes. breast cancer, or blood clots. Using estrogens with progestins may increase your chance of getting dementia. based on a study of women 65 years of age or older. Do not use estrogen-alone to prevent heart disease. heart attacks. strokes, or dementia.

INDICATIONS FOR NATAZIA®

Natazia is indicated for use by women to prevent pregnancy.

Natazia is also indicated for the treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of birth control.

The contraceptive efficacy of Natazia in women with a body mass index (BMI) of >30 kg/m2 has not been evaluated.


IMPORTANT SAFETY INFORMATION

Women over 35 years old who smoke should not use Natazia. Smoking increases the risk of serious cardiovascular side effects from Natazia use. This risk increases with age and the number of cigarettes smoked.

Patients who should not take Natazia

Natazia should not be used in women with a high risk of arterial or venous thrombotic diseases, undiagnosed abnormal uterine bleeding, breast cancer or other estrogen- or progestin-sensitive cancer, liver tumors (benign or malignant) or liver disease, or who are pregnant.

Know the most serious risks

Thromboembolic and Other Vascular Events: Stop Natazia if an arterial or venous thrombotic event occurs. The risk of venous thromboembolism (VTE) is highest during the first year of combination oral contraceptive (COC) use. This increased risk is greatest after initially starting a COC or restarting the same or a different COC following a 4 week or greater pill-free interval.

COC use also increases the risk of arterial thromboses (eg, stroke and myocardial infarction) especially in women with other risk factors for these events. If feasible, stop Natazia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding. COCs must be used with caution in women with cardiovascular disease risk factors.

Liver Disease: Discontinue Natazia if jaundice develops. Hepatic adenomas are associated with COC use.

High Blood Pressure (BP): For women with well-controlled hypertension, monitor blood pressure and stop Natazia if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.

Carbohydrate and Lipid Metabolic Effects: Carefully monitor prediabetic and diabetic COC users. Consider alternative contraception for women with uncontrolled dyslipidemia.

Headache: If a Natazia user develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Natazia if indicated. Increased frequency or severity of migraines may be reason for immediate discontinuation.

Bleeding Irregularities: If irregular bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. Rule out pregnancy in the event of amenorrhea occurring in 2 or more consecutive cycles.

Drug Interactions: Women taking strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should not use Natazia during and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy.

Counsel patients that Natazia does not protect against HIV infection and other sexually transmitted diseases.

Serious adverse reactions in clinical trials

Myocardial infarction, ruptured ovarian cyst, deep vein thrombosis, focal nodular hyperplasia of the liver, uterine leiomyoma, acute cholecystitis, and chronic acalculous cholecystitis .

Most common adverse reactions (≥2%) in clinical trials

Headache (including migraines) (12.7%), breast pain, discomfort or tenderness (7.0%), menstrual disorders (6.9%), nausea or vomiting (6.0%), acne (3.9%), mood changes (3.0%), and increased weight (2.9%).

Please see Full Prescribing Information for Natazia, including Boxed Warning.

INDICATIONS FOR CLIMARA PRO®

In women with an intact uterus, Climara Prot (estradiol/levonorgestrel transdermal system) is indicated for treatment of moderate to severe vasomotor symptoms due to menopause. Climara Pro is also indicated for the prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.


IMPORTANT SAFETY INFORMATION

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA

Estrogen Plus Progestm Therapy

Cardiovascular Disorders and Probable Dementia

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].

The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to n years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].

The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].

 

Breast Cancer

The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.5)].

In the absence of comparable data. these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen-Alone Therapy

 

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.2)].

 

Cardiovascular Disorders and Probable Dementia

Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.1, 5.3), and Clinical Studies (14.5, 14.6)].

The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.5)].

The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.6)].

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other forms of estrogens.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

CONTRAINDICATIONS

Climara Pro is contraindicated in women with any of the following conditions: undiagnosed abnormal genital bleeding, known, suspected, or history of breast cancer, known or suspected estrogen-dependent neoplasis, active deep vein thrombosis, pulmonary emboli or a history of these conditions, active artenal thromboembolic disease (e.g. stroke, myocardial infarction), or a history of these conditions, known anaphylactic reaction or angioedema with Climara Pro, known liver impairment or disease, known protein C, protein S. or antithrombin deficiency, or other known thrombophilic disorders, known or suspected pregnancy.

WARNINGS AND PRECAUTIONS

Cardiovascular Disorders: An increased risk of cardiovascular events such as MI PE, DVT, VTE, stroke and MI has been associated with estrogen and estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued Immediately. Risk factors for arterial vascular disease ( for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. If feasible, Climara Pro should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant Neoplasia: The use of estrogens and progesbns by postmenopausal women has been reported to increase the risk of breast cancer. After a mean follow-up of 5 6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammography results. The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The greatest risk appears to be associated with prolonged use and may persist for at least 8 to 15 years after discontinuation. Adding a progestin to estrogen therapy has been shown to reduce the risk of endomethal hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the nsk of endometnal hyperplasia, which may be a precursor to endometrial cancer. Estrogens with or without progestin may increase the risk of ovarian cancer.

Probable Dementia: Climara Pro should not be used for the prevention of dementia (see Boxed Warning)

Gallbladder Disease: An increased risk of gallbladder disease which may require surgery has been reported in postmenopausal women receiving estrogens.

Hypercalcomta: Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium levels.

Visual Abnormalities: Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Estrogens should be permanently discontinued if papilledema or retinal lesions are detected.

Addition of a Progostin Whon a Woman Has Not Had a Hysterectomy
Studies of the addition cf a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen. have reported a lowered incidence of endometnal hyperplasia than would be induced by estrogen treatment alone. Endometnal hyperplasia may be a precursor to endometrial cancer.

Elevated Blood Pressure: In a small number of case reports, increases in blood pressure have been attributed to idiosyncratic reactions to estrogens.

Hypertriglyceridemla: Increased plasma triglycerides leading to pancreatitis may occur with estrogens in women with preexisting hypertnglycendemia. Consider discontinuation of treatment if pancreabtis occurs.

Liver Disease: Discontinue Climara Pro if cholestatic jaundice occurs.

Hypothyroidism: Increased thyroid-binding globulin levels may occur. Monitor thyroid function in women on thyroid replacement therapy.

Fluid retention: Estrogens plus progestins may cause fluid retention; monitoring may be warranted.

Hypocalcemia: Use Cliinara Pro with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

Exacerbation of Endometriosis: A few cases of malignant transformation of residual endometnal implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometnosis post-hysterectomy, the addition of progestin should be considered.

Hereditary Angloedema: Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Exacerbation of other conditions: Estrogen therapy may cause an exacerbation of asthma, diabetes, mellitus, epilepsy, migraine or porphyna, systemic lupus erythematosus, and hepatic hemangiomas. Estrogens should be used with caution in women with these conditions.

ADVERSE REACTIONS

Toe most common adverse reactions (≥5%) in clinical trials were: application site reaction, vaginal bleeding, breast pain. upper respiratory infection, back pain, depression pain, and headache.

For important risk and use information about Climara Pro, including Boxed Warning, please see the Full Prescribing Information

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